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cAMP and Schwann cells promote axonal growth and functional recovery after spinal cord injury

Nature Medicine volume 10, pages 610–616 (2004)Cite this article

Abstract

Central neurons regenerate axons if a permissive environment is provided; after spinal cord injury, however, inhibitory molecules are present that make the local environment nonpermissive. A promising new strategy for inducing neurons to overcome inhibitory signals is to activate cAMP signaling. Here we show thatcAMP levels fall in the rostral spinal cord, sensorimotor cortex and brainstem after spinal cord contusion. Inhibition of cAMP hydrolysis by the phosphodiesterase IV inhibitor rolipram prevents this decrease and when combined with Schwann cell grafts promotes significant supraspinal and proprioceptive axon sparing and myelination. Furthermore, combining rolipram with an injection of db-cAMP near the graft not only prevents the drop in cAMP levels but increases them above those in uninjured controls. This further enhances axonal sparing and myelination, promotes growth of serotonergic fibers into and beyond grafts, and significantly improves locomotion. These findings show that cAMP levels are key for protection, growth and myelination of injured CNS axons in vivo and recovery of function.

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Figure 1: Rolipram and db-cAMP prevent SCI-induced reductions in cAMP.
Figure 2: Acute rolipram inhibits TNF-α, but not IL-1β, production hours after SCI.
Figure 3: Elevation of cAMP promotes central myelinated axon preservation, axonal growth regeneration and SC myelination.
Figure 4: Elevation of cAMP supports supraspinal axon sparing and growth.
Figure 5: Elevation of cAMP promotes serotonergic growth into and beyond SC grafts.
Figure 6: Improved functional recovery after prolonged cAMP elevation.

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Acknowledgements

We thank R. Puzis and M. Perez for help with immunochemistry and ELISAs; Y. Pressman for SC culturing; B. Frydel, M. Garg and A. Stolyarova for aid with image analysis; G. Ruenes, L. Rusakova, W. Chen and X. Zhang for tissue embedding and sectioning; Y. Cruz for expertise in statistical analyses; E. Nikulina for helpful discussions on rolipram administration; R. Abril, D. Koivisto and K. Loor for help with animal care and behavioral testing; and P. Diaz and S. Castro for inducing contusion injuries and drug treatment. Anti-p75 (192 IgG) was a gift from E. Shooter (Stanford University, Stanford, California, USA). This work was funded by the Christopher Reeve Paralysis Foundation, NINDS09923 and 38665, The Miami Project and the Buoniconti Fund. D.D.P. is a Christopher Reeve Paralysis Foundation Consortium Associate. M.B.B. is the Christine E. Lynn Distinguished Professor of Neuroscience.

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Authors and Affiliations

  1. The Miami Project to Cure Paralysis, University of Miami School of Medicine, 1095 NW 14th Terrace, Miami, 33136, Florida, USA

    Damien D Pearse, Alexander E Marcillo, Margaret L Bates, Yerko A Berrocal & Mary Bartlett Bunge

  2. Department of Anatomy, Institute of Biomedical Sciences, University of Sao Paulo, Av. Prof. Lineu Prestes, 2415, Sao Paulo, 05508-900, CEP, Brazil

    Francisco C Pereira

  3. Biology Department, Hunter College, 695 Park Ave., New York, 10021, New York, USA

    Marie T Filbin

  4. Department of Cell Biology and Anatomy, University of Miami School of Medicine, Miami, 33136, Florida, USA

    Mary Bartlett Bunge

  5. Department of Neurological Surgery, University of Miami School of Medicine, Miami, 33136, Florida, USA

    Mary Bartlett Bunge

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Correspondence to Damien D Pearse.

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Pearse, D., Pereira, F., Marcillo, A. et al. cAMP and Schwann cells promote axonal growth and functional recovery after spinal cord injury. Nat Med 10, 610–616 (2004). https://doi.org/10.1038/nm1056

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